Therapeutic hypothermia (TH) is widely used to reduce oxygen requirements and to protect organs from ischemia. In cardiac surgery hypothermia is typically established temporarily with the heart lung machine during cardiopulmonary bypass (CPB), and deep hypothermic circulatory arrest (DHCA) is an important component of surgery for congenital heart disease. DHCA is also used in adult patients for the repair of thoracic aortic dissections as well as in neurosurgical operations for the treatment of cerebral aneurysm.
TH employed in clinical settings has also been associated with platelet activation, aggregation, sequestration, and (micro)vascular thrombus formation, due to the conformational change of integrin GPIIb/IIIa from a low to a high affinity state for the plasma protein fibrinogen. This may result in fatal thrombotic events, thrombocytopenia, as well as severe bleeding complications. Therefore, thus there is a need for novel therapeutic approaches that prevent platelet-related coagulation disturbances associated with hypothermia.
Preoperative treatment with the GPIIb/IIIa blockers, tirofiban and eptifibatide, has been reported to preserve platelet function during CPB. However, a significant side effect of the currently used intravenous therapeutic strategies for GPIIb/IIIa inhibition during hypothermia is their inhibitory effect on all circulating platelets with a consecutive risk for bleeding complications. Therefore, the current intravenous GPIIb/IIIa blockers have significant limitations. Thus there is a substantial need for a safer and more efficient pharmacological approach. A single-chain antibody directed against GPIIb/IIIa that selectively blocks the activated form of the receptor only has been described. See Schwarz et al., Circ Res., 2006, 99:25-33 and Stoll et al., Arterioscler Thromb Vasc Biol., 2007, 27:1206-1212.
Short elastin-like peptides exhibit the similar temperature-induced structural transitions as elastin polymers. See Reiersen et al., J Mol. Biol., 1998, 283:255-264. Temperature-responsive elastin-like polypeptide linkers have been disclosed to modulate single-chain antibody affinity. See Megeed et al., Biomacro-molecules, 2006, 7:999-1004.